Objective:To investigate the relationship between serum homocysteine (HCY), folate (FOL) and methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C gene polymorphism in patients with type 2 diabetic nephropathy (DN).Methods:A total of 161 patients with type 2 diabetes diagnosed in Jiangsu Shengze Hospital between January 2017 and December 2018, including 81 DN (41 males, 40 females; age: (61.5±14.2) years), 80 diabetic mellitus without nephropathy (DM; 42 males, 38 females, age: (57.7±10.8) years), and 77 normal controls (NC; 39 males, 38 females, age: (58.2±16.3) years) were retrospectively analyzed. The serum levels of HCY and FOL were detected by enzyme circulation and electrochemiluminescence respectively. TaqMan genotyping technique was used to detect MTHFR 677T&A1298 gene polymorphism. The serum levels of HCY and FOL were compared with one-way analysis of variance (the least significant difference t test), and the distribution differences of MTHFR gene were analyzed by χ2 test. Results:The difference of HCY level among DN, DM and NC groups was significantly different ((19.76±7.81), (15.62±5.01) and (8.09±3.74) μmol/L; F=81.738, P<0.001). The FOL level among the 3 groups was also significantly different ((12.18±3.01), (13.50±2.71) and (15.43±2.95) μg/L; F=26.978, P<0.001). The frequencies of 677T allele (51.2%, 83/162), 677TT/1298AA genotype (25.9%, 21/81) in DN group were significantly higher than those in DM (33.1%, 53/160; 11.2%, 9/80) and NC (33.8%, 52/154; 10.4%, 8/77) groups ( χ2 values: 10.821, 9.099, both P<0.05), but the 1298C allele frequency was not significantly different among the 3 groups (21.6%(35/162, DN) vs 16.9%(27/160, DM) vs 18.2%(28/154, NC); χ2=1.269, P>0.05). The levels of HCY and FOL in individuals with 677TT/1298AA genotype were significantly higher than those in individuals with other genotypes ( F values: 12.955, 15.504, all P<0.05). Conclusion:The abnormal metabolism of HCY and FOL caused by MTHFR C677T&A1298C gene polymorphism may be the genetic risk factor of DN.